The objective of the Tumor Microenvironment and Metastasis Program is to understand the molecular mechanisms involved in the regulation of the survival, differentiation and function of cells in tumors, the microenvironments responsible for invasion and metastasis, and signaling pathways employed. The program is supported by a Program Project grant focused on defining how signaling pathways in macrophages and carcinoma cells contribute to the motility and chemotatic behaviors that generate the invasive phenotype. The major disease site studied is breast but other cancers such as lung are also included. The program has three major goals: (1) Dissection of the role the microenvironment plays in tumor progression and metastasis: There is an emphasis on the interaction between tumor cells and tumor associated macrophages, cells that promote tumor progression and metastasis. These studies utilize, xenotransplants, mouse models, as well as human tumor xenotransplants into immunocompromised mice. Six distinct functions have been identified for macrophages in promoting malignancy. 2) The molecular mechanisms of growth factor and hormone action in regulating cell motility and proliferation. Investigators study the intrinsic mechanisms that feed downstream from receptors in regulating cell motility, chemotaxis, invasion as well as cell proliferation. There is a particular emphasis on signaling from the colony stimulating factor receptor in macrophages and the ErbB family of receptors in tumor cells and the studies utilize a combination of systems, including cell lines in culture and as xenografts, as well as mouse models of breast cancer. 3) Imaging and animal models. This is directed to the development of innovative optical technologies using multiphoton microscopy to image cells and their interactions within the tumor microenvironment in vivo coupled with innovative mouse genetics to label lineages and perturb signaling pathways. There are currently 21 program members from 10 departments, of whom 16 are primary members, supported by 17 NCI ($2.9M Direct) and 10 other NIH grants. There have been 8 new recruits to this program. Since the last CCSG review there have been 246 cancer-relevant research papers by members of this program of which 20% represent intraprogrammatic, and 21% represent interprogrammatic collaborations.